Sensors for analysing body fluids are often principal components of clinically relevant analytical methods. In this connection a rapid and precise measurement of analytes is of primary interest that allows the determination of so-called point-of-care parameters. Point-of-care examinations are often carried out above all in intensive care units and in anaesthesia departments, but also in outpatient departments. These so-called emergency parameters include among others the blood gas values (and here in particular the oxygen content and carbon dioxide content), the pH value, electrolyte values as well as certain metabolite values.
Point-of-care examinations have the advantage that the results are already available after a short time because, on the one hand, the samples do not have to be transported to a specialized laboratory and, on the other hand, one does not have to allow for the time schedules of the laboratory. In order to enable emergency parameters to be determined as near as possible in time, sensors are used that are designed for a multiple analyte determination, which sensors should in principle have a high in-use lifetime in order to increase the period between regular sensor replacements, which are for example required after a predetermined maximum period of use has expired or after a predetermined number of measurements have been carried out. This reduces the time needed for the sensor replacement during which such a point-of-care analyzer is not able to be used, i.e., is not available for measurements. Furthermore, the sensor activation time that directly follows a sensor replacement, which specifies the time period from the sensor replacement until a new sensor is able to be used for analytical measurements, should be kept as short as possible.
Test strips and also medical analyzers with multi-use sensors can for example be used to carry out such point-of-care examinations, which reduces the manual labor for carrying out the examinations to a minimum. Sensors for a point-of-care use are usually operated in an almost completely automated manner in appropriately equipped analytical measuring devices and often require only a few and simple interventions by the user from the sample preparation up to the provision of the test result. They can be designed for a single as well as for a repeated measurement of the parameters to be determined.
The measurement of oxygen or its partial pressure (pO2) in an aqueous measuring medium can for example be carried out using amperometric sensors comprising at least one working electrode and at least one counter electrode. In the case of electrodes of the Clark type, a gas-permeable and a substantially ion-impermeable and liquid-impermeable membrane spatially separates the sample space from the inner electrolyte space. The inner electrolyte space is filled with an electrolyte solution in which a working electrode and a counter electrode are located. An electrode arrangement with a microporous inner electrolyte layer is described in, for example, WO 2009/090094 A1.
An important criterion in the development and provision of electrochemical sensors for point-of-care examinations are the special requirements regarding the measuring conditions and in particular regarding the usually only small volume of sample that is available. Thus, generally only small amounts of sample (e.g., 100 μl or less) are available for the determination of emergency parameters. If it is intended to determine a large number of parameters using small amounts of sample, the individual electrodes and the distances between them should be as small as possible.
Another important criterion in the development and provision of electrochemical sensors for point-of-care examinations is, as mentioned above, their lifetime. In this connection there is the need to achieve a long-lasting shelf life before the sensor is put into operation as well as a high in-use lifetime of the electrochemical sensor.
In order to ensure a long-lasting shelf life, the electrodes located in the electrochemical sensor should be stored dry, i.e., essentially free of water, and only be brought into contact with the liquid inner electrolyte directly before they are put into operation. For this purpose the liquid inner electrolyte can for example be formed in situ by contacting the dry sensor with an aqueous solution before start-up whereby water diffuses into the inner electrolyte space and dissolved ions located there with formation of the liquid inner electrolyte.
In order to achieve a high in-use lifetime of for example at least 500 measurements or 3 to 4 weeks, as is desired for modern point-of-care analyzers, the various layers of the electrochemical sensor must also be compatible with one another. Thus, in particular they should not become detached from one another or form cracks such as can for example be caused by swelling.
Finally, as explained above, the ability to rapidly activate an electrochemical sensor that is being used for the first time for analytical measurements in an analyzer plays an important role. Hence, in order to enable analytes in a sample to be rapidly determined, the time period between inserting a new electrochemical sensor into an analyzer and its being available for use for analytical measurements should be as short as possible.
EP 0 805 973 B1 discloses a device as well as a method for measuring the concentration of gases in a sample. An electrochemical sensor serves as the device which comprises a working electrode, a counter electrode, an electrolyte layer and a gas-permeable membrane where the electrolyte layer consists of a photo-formed proteinaceous gel. In order to prevent a premature contamination of the negatively polarized working electrode (cathode) consisting of gold by positively charged silver ions originating from the counter electrode (anode) consisting of silver, the spacing between the two electrodes that are in electrical contact via a gel layer must be at least 1 mm.
U.S. Pat. No. 5,387,329 describes a planar electrochemical oxygen sensor in which a swellable polymer whose swelling rate is less than twice its dry volume is used as a hygroscopic electrolyte, and in this process forms a hydrophilic electrolyte layer that is permeable to water and cations. A swellable polymer that is preferred in the context of this document is Nafion®, a sulfonated tetrafluoroethylene polymer whose lithium charged sulfonate groups give the polymer ionomeric properties and result in an exchange of lithium ions for silver ions. This has the effect that in the case of an amperometric oxygen sensor with a silver counter electrode, the effective migration rate of the silver ions to the working electrode is lowered.
The electrolyte layers used in EP 0 805 973 B1 and U.S. Pat. No. 5,387,329 have disadvantages. Thus, for example, the production of very thin layers (about 1 μm) of swellable polymers (such as, e.g., the photo-formed proteinaceous gels in EP 0 805 973 B1) is very laborious.
Furthermore, the silver ions released during the operation of an oxygen sensor rapidly lead to interfering signals as well as an increase of the measurement signal and of the zero point in the case of very thin layers and very small electrolyte volumes, where the zero point specifies the current which flows across the oxygen sensor at 0% oxygen in the sample. On the other hand, the use of thicker, swelling layers (about 10-50 μm) in a multilayer construction promotes the formation of leaks in the layer structure. This makes it difficult to achieve the desired long-life of the sensor.
An important disadvantage of thin, water-containing polymer layers is also that, after applying an electrical field, interfering silver ions migrate between the two electrodes on a direct path through the polymer and thus reach the working electrode and contaminate it after a relatively short operating period which considerably limits the effective period of use of such preferably planar oxygen sensors.
WO 2009/090094 A1 discloses an electrochemical sensor in which the disadvantages described above are at least partially eliminated. For this purpose the electrochemical sensor contains an electrolyte layer located between the working electrode and the counter electrode, the electrolyte layer comprising at least one particulate material and at least one binding agent. In this case the particulate material which is preferably an alumosilicate such as, for example, a zeolite and the binding agent forms a microporous layer which then can be permeated by a liquid electrolyte.
In contrast to a gel-like electrolyte layer as described for example in EP 0 805 973 B1, silver ions generated at the counter electrode of such an electrochemical sensor have to migrate through a labyrinth of micropores on their way to the working electrode which slows down the migration rate of the silver ions. Furthermore, in a preferred variant WO 2009/090094 A1 provides the possibility that the particulate material additionally has ion-exchange groups to which the silver ions can at least temporarily bind. These two measures can increase the lifetime of the electrochemical sensor to about three to four weeks.